Download Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms

Benign Prostatic Hyperplasia and
Lower Urinary Tract Symptoms
March 26, 2014
7:45 AM – 9:00 AM
Anaheim, California
Sponsored by pmiCME
Educational Partner
Session 1: The Evaluation and Treatment of Benign Prostatic Hyperplasia and Lower Urinary
Tract Symptoms in the Primary Care Setting
Learning Objectives
1.
2.
3.
Describe the pathophysiology and common comorbidities of benign prostatic hyperplasia and lower urinary
tract symptoms (BPH/LUTS)
Implement comprehensive assessment of patients with BPH/LUTS
Select treatment options available to effectively treat BPH/LUTS
Faculty
Martin Miner, MD
Chief of Primary Care and Community Medicine
The Miriam Hospital
Co-Director
Men’s Health Center
Clinical Associate Professor of Family Medicine and Urology
Warren Alpert Medical School
Brown University
Providence, Rhode Island
Dr Martin Miner clinical associate professor of family medicine and urology at Warren Alpert Medical School, Providence,
Rhode Island, has practiced preventive and primary care medicine for more than 28 years and is currently chief of family
and community medicine at The Miriam Hospital. He is the author of more than 75 publications in the areas of erectile
dysfunction and cardiovascular disease, benign prostatic hyperplasia and lower urinary tract symptoms in reference to
male sexuality, and hormonal replacement therapy in men. Dr Miner is president elect of the American Society for Men’s
Health, associate editor of the Journal of Men’s Health, and serves on multiple journal boards and reviews for several
publications. He is currently active in several research studies on men’s health, and was the recipient of the dean’s
teaching excellence award in 2003 and 2007.
Matt T. Rosenberg, MD
Medical Director
Mid-Michigan Health Centers
Chief, Department of Family Medicine
Foote Health System
Jackson, Michigan
Dr Matt Rosenberg earned his medical degree at the University of California, Irvine, where he trained in general surgery.
He also trained in urologic surgery at Brigham and Women’s Hospital, Boston before changing fields to general practice.
Dr Rosenberg has a special interest in the medical management of urologic diseases and has authored or coauthored
articles appearing in Urology, Journal of Urology, BJU International, International Journal of Clinical Practice, and other peer
reviewed journals. He now practices in Jackson, Michigan; serving as medical director of Mid-Michigan Health Centers,
and on staff at Allegiance Health, where he served as chief of the department of family medicine from 2003 to 2006. Dr
Rosenberg is section editor of urology at the International Journal of Clinical Practice and is founder and chairman of the
Session 1
Urologic Health Foundation: a nonprofit group dedicated to the education of primary care physicians in the field of
genitourinary disease. In 2011, he was appointed by the American Urological Association office of education to be the
Coordinator of Primary Care Education.
Faculty Financial Disclosure Statements
The presenting faculty reported the following:
Dr Miner receives consultant honoraria from AbbVie and research funding from Forest.
Dr Rosenberg receives consultant and speaker honoraria from Astellas, Eisai, Ferring, Forest, Horizon, Ortho-McNeil, Lily,
and Pfizer.
Education Partner Financial Disclosure Statement
The content collaborators at Miller Medical Communications, LLC, report the following:
Lyerka D. Miller, PhD, has no financial relationships to disclose.
Suggested Reading List
Issa MM, Fenter TC, Black L, Grogg AL, Kruep EJ. An assessment of the diagnosed prevalence of diseases in men 50 years
of age or older. Am J Manag Care. 2006;12(4 suppl):S83-S89.
Bushman W. Etiology, epidemiology, and natural history of benign prostatic hyperplasia. Urol Clin North Am.
2009;36(4):403-415.
Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of
the aging male (MSAM-7). Eur Urol. 2003;44(6):637-649.
Rosenberg MT, Miner MM, Riley PA, Staskin DR. STEP: simplified treatment of the enlarged prostate. Int J Clin Pract.
2010;64(4):488-496.
McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA guideline on the management of benign prostatic hyperplasia.
J Urol. 2011;185(5):1793-1803.
Lee RK, Chung D, Chughtai B, Te AE, Kaplan SA. Central obesity as measured by waist circumference is predictive of
severity of lower urinary tract symptoms. BJU Int. 2012;110(4):540-545.
Kupelian V, McVary KT, Kaplan SA, et al. Association of lower urinary tract symptoms and the metabolic syndrome: results
from the Boston area community health survey. J Urol. 2013;189(1 Suppl):S107-S114.
Elterman DS, Barkin J, Kaplan SA. Optimizing the management of benign prostatic hyperplasia. Ther Adv Urol. 2012;4(2):7783.
Rosenberg MT, Staskin D, Riley J, Sant G, Miner M. The evaluation and treatment of prostate-related LUTS in the primary
care setting: the next STEP. Curr Urol Rep. 2013;14(6):595-605.
Gacci M, Corona G, Salvi M, et al. A systematic review and meta-analysis on the use of phospodiesterase 5 inhibitors alone
or in combination with -blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol.
2012;61(5):994-1003.
Lythgoe C, McVary KT. The use of PDE-5 inhibitors in the treatment of lower urinary tract symptoms due to benign
prostatic hyperplasia. Curr Urol Rep. 2013;14(6):585-594.
Kapoor A. Benign prostatic hyperplasia (BPH) management in the primary care setting. Can J Urol. 2012;19 (Suppl 1):10-17.
Session 1
Kaplan SA, Wein AJ, Staskin DR, Roehrborn CG, Steers WD. Urinary retention and post-void residual urine in men:
separating truth from tradition. J Urol. 2008;180(1):47-54.
Casabé A, Roehrborn CG, Da Pozzo LF, et al. Efficacy and safety of the coadministration of tadalafil once daily with
finasteride for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to benign
prostatic hyperplasia. J Urol. 2014;191(3):727-733.
McConnell JD, Roehrborn CG, Bautista OM, et al; for the Medical Therapy of Prostatic Symptoms (MTOPS) Research Group.
The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic
hyperplasia. N Engl J Med. 2003;349(25):2387-2398.
Fourcade RO, Lacoin F, Rouprêt M, et al. Outcomes and general health-related quality of life among patients medically
treated in general daily practice for lower urinary tract symptoms due to benign prostatic hyperplasia. World J Urol.
2012;30(3):419-426.
Session 1
Presenter Disclosure Information
SESSION 1
The following relationships exist related to this presentation:
7:45–9am
► Dr Rosenberg has served as a consultant or speaker for Astellas,
Eisai, Ferring, Forest, Horizon, Lilly, Ortho-McNeil, and Pfizer.
The Evaluation and Treatment of
Benign Prostatic Hyperplasia and
Lower Urinary Tract Symptoms
in the Primary Care Setting
► Dr Miner has served as a consultant for AbbVie and has received
research funding from Forest.
Off-Label/Investigational Discussion
SPEAKERS
► In accordance with pmiCME policy, faculty have been asked to
disclose discussion of unlabeled or unapproved use(s) of drugs or
devices during the course of their presentations.
Matt T. Rosenberg, MD
Martin Miner, MD
Drug List
Generic Name
Faculty
Fortamet, Glucophage, Glucophage XR, Glumetza
Linagliptin
Tradjenta
Enalapril
Epaned, Vasotec
Atorvastatin
Lipitor
Alfuzosin
Matt T. Rosenberg, MD
Martin Miner, MD
Chief of Primary Care and Community Medicine
The Miriam Hospital
Co-Director, Men’s Health Center
Clinical Associate Professor of Family Medicine
and Urology
Warren Alpert Medical School
Brown University
Providence, Rhode Island
Medical Director
Mid-Michigan Health Centers
Chief
Department of Family Medicine
Foote Health System
Jackson, Michigan
Learning Objectives
Implement comprehensive assessment of
patients with BPH/LUTS
•
Select treatment options available to effectively
treat BPH/LUTS
Cardura
Silodosin
Rapaflo
Tamsulosin
Flomax
Terazosin
Hytrin
Tadalafil
Adcirca, Cialis
Detrol, Detrol LA, Detrusitol
Trospium chloride
Sanctura, Spasmex, Spasmolyt, Trosec
Darifenacin
Enablex
Fesoterodine
Toviaz
Oxybutynin
Ditropan, Gelnique, Lyrinel XL, Oxytrol
Solifenacin
VesiCare
Mirabegron
Myrbetriq
Dutasteride
Avodart
Finasteride
Proscar
Dutasteride/Finasteride
Jalyn
4
Myths
After participating in this educational activity
the participant should be able to:
• Describe the pathophysiology and common
comorbidities of BPH/LUTS
•
Uroxatral
Doxazosin
Tolterodine
3
Trade Name
Metformin
•
•
•
LUTS in the male is a normal part of aging
•
PSA testing has no use in the evaluation of LUTS
LUTS in the male is always related to the prostate
The provider needs urodynamic testing to facilitate
the diagnosis LUTS
BPH=benign prostatic hyperplasia; LUTS=lower urinary tract symptoms.
5
10
1
Realities
•
•
•
•
A Typical Patient?
•
LUTS in the male is not a normal part of aging
LUTS can come from the bladder, prostate, or
medical causes
The evaluation of LUTS can be performed in the
PCP office with an adequate history, physical,
and a few simple labs
The PSA is a surrogate marker for prostate size
•
Stephen is a 65-year-old obese, hypertensive
male with type 2 DM
At the encouragement of his wife, he admits
that he has some issues “down there”
– He complains of urinary urgency, a poor stream,
frequency, and nocturia
– He has tolerated these symptoms for several years
as he thought it was a natural part of aging
PCP=primary care physician.
DM=diabetes mellitus.
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12
Current Medications
•
•
•
•
Physical Examination
•
•
•
•
Metformin 500 mg twice daily
Linagliptin 5 mg daily
Enalapril 10 mg daily
Atorvastatin 10 mg daily
•
•
•
•
Height: 5’ 9”
Weight: 217 lb
BMI: 32 kg/m2
BP: 140/80 mm Hg
Neck: No thyromegaly
Lungs: Clear
Cor S1S2S4
Genital: testes descended, no
masses, no varicocele, normal
size (30-35 g); no prostate
nodule palpated
•
•
•
•
Feet: no ulcers
Neurologic: mild decreased
sensation to 10-g monofilament;
no visual field cuts
Skin/hair: normal beard, normal
male pattern hair in genital axilla
No gynecomastia
BP=blood pressure.
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14
Laboratory Results
•
•
•
•
•
•
•
•
•
CLUES in the Patient Presentation
•
HbA1C: 6.8% at his last check-up 6 months ago
Cr: 1.3 mg/dL
PSA: 1.7 ng/mL
TC: 210 mg/dL
LDL-C: 110 mg/dL
HDL-C: 35 mg/dL
TG: 250 mg/dL
Microalbumin: undetectable
GFR: 50 mL/min
•
Stephen is a 65-year-old obese, hypertensive
male with type 2 DM
At the encouragement of his wife, he admits that
he has some issues “down there”
– He complains of urinary urgency, a poor stream,
frequency, and nocturia
– He has tolerated these symptoms for several years
as he thought it was a natural part of aging
15
17
2
Function of the Prostate
More Clues
•
•
•
•
•
•
•
•
•
HbA1C: 6.8% at his last check-up 6 months ago
Cr: 1.3 mg/dL
PSA: 1.7 ng/mL
TC: 210 mg/dL
LDL-C: 110 mg/dL
HDL-C: 35 mg/dL
TG: 250 mg/dL
Microalbumin: undetectable
GFR: 50 mL/min
Normal Function
Abnormal Function
•
•
•
•
Obstruction of urinary
flow
Poor function seen as
failure to void
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
18
Benign Prostatic Hyperplasia
•
Produces fluid for
seminal emission
Does not compress the
urethra, thereby allowing
unobstructed flow
19
Natural History of Prostate Growth
•
A common condition as men age
– By sixth decade: >50% of men have some
degree of hyperplasia
According to data from a study by Roehrborn and colleagues, a 55-year–old
man who has a 30-mL prostate volume (PV), is experiencing symptoms, and
has a PSA of 1.5 ng/mL can expect his prostate to approximately double in
size over the next 15 years.
– By eighth decade: >90% of men will have hyperplasia
•
In only a minority of patients (approximately
10%) will this hyperplasia be symptomatic and
severe enough to require medical treatment or
surgical intervention
Age
55 yrs
60 yrs
65 yrs
70 yrs
PV
30 mL
>40 mL
>50 mL
>61 mL
PSA
McVary KT, et al. J Urol. 2011;185(5):1793-1803..
Increase in bother
Decrease in quality
of life
21
Risk Evaluation of BPH-LUTS Progression
Complications of BPH Progression
Worsening of
symptoms
1.5 ng/mL
Roehrborn C, et al. J Urol. 2000;163(1):13-20.
20
Baseline Factors as Predictors
Five risk factors
The
Enlarging
Prostate
1. Total prostate volume ≥31 mL
Need for surgical
intervention
2. PSA ≥1.6 ng/mL
3. Age ≥62
Not usually evaluated by the PCP
Alarm symptoms
4. Qmax <10.6 mL/s
Hematuria
Acute urinary retention
UTI
Bladder stones
Renal failure
5. PVR ≥39 mL
PVR=post-void residual; Qmax=maximum flow rate.
UTI=urinary tract infection.
Roehrborn CG, McConnell JD. In: Walsh PC, et al. Campbell’s Urology. 8th ed. Philadelphia, PA:
Saunders; 2002:1297-1330.
Crawford ED, et al. J Urol. 2006;175(4):1422-1427.
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
22
3
23
Function of the Bladder
Assessment: DRE vs PSA
•
There is a strong and clinically useful relationship between serum
PSA and prostate volume, which enables the clinician to estimate
prostate size in men with LUTS and BPH, and also to identify men
with prostate above certain thresholds
•
Digital rectal examination (DRE) is quite inaccurate in estimating
the correct prostate size when compared with either transrectal
ultrasound (TRUS) or other imaging modalities
Roehrborn CG. Int J Impot Res. 2008;20 suppl 3:S19-S26.
Normal Function
• Storage capacity of
300500 mL of fluid
•
Uncontrollable urge
(urgency) to empty
•
•
Incomplete emptying
Poor function seen as
failure to store
25
Focus on the Prostate May Lead to
Missed Treatment Opportunities
Definition of OAB
•
65% of patients with bladder outlet obstruction (BOO)
and detrusor overactivity (DO) treated with an -blocker
for 3 months did not show improvement in symptoms
Urinary frequency (voiding often during the day)
•
Nocturia (wakening at night to void)
19% of men have persistent OAB symptoms after
prostate surgery
•
83% of men who experience resolution of OAB
symptoms after TURP have return of symptoms at
long-term follow-up
A syndrome including:
•
•
•
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
24
International Continence Society (ICS)
•
Empty to completion
after a gentle urge
Abnormal Function
• Voiding frequently of
small amounts (less
than capacity)
Urinary urgency (the intense, sudden desire to
void) with or without incontinence
– Of these, 73% improved after adding antimuscarinic
BOO=bladder outlet obstruction; DO=detrusor overactivity; TURP=transurethral resection of prostate.
Lee JY, et al. BJU Int. 2004;94(6):817-820.
Dmochowski RR, et al. Urology. 2002;60(5 suppl 1):56-62.
Thomas AW et al. J Urol. 1999;161:257.
OAB=overactive bladder.
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
26
Using Symptoms to Distinguish the
Origin of the Problem
Urine Storage
Differentiating the Etiology of LUTS
•
•
•
•
Urine Voiding
Urgency
Hesitancy
Frequency
Weak stream
Urgency incontinence
Intermittent
Nocturia
Straining
27
Weak flow – think prostate
Voiding small amounts – think bladder
Leakage of urine – think bladder or sphincter
Good flow, normal volume – think too much fluid
production and evaluate accordingly
It is all about volume and flow
Kapoor A. Can J Urol. 2012;19 suppl 1:10-17.
Abrams P, et al; Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn.
2002;21(2):167-178.
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
28
4
29
Common Comorbidities in
BPH-LUTS
OAB and BPH Can Coexist
LUTS
OAB
BPH
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
LUTS-BPH and ED
Comorbidities
• Cardiovascular disease
• Diabetes/Disrupted
glucose homeostasis
• Erectile dysfunction
• Metabolic syndrome
• Obesity
ED
Risk Factors
• Increasing age
• Smoking
• High waist
circumference
Comorbidities
Cardiovascular disease
Depression
Diabetes
Hypercholesterolemia
Lower urinary tract
symptoms
• Metabolic syndrome
• Obesity
36
Digestive tract disorder
21
Arthritis
20
Heart disease/Heart failure
18
Diabetes
17
Depression/Anxiety/Sleep disorder
16
Allergies/Cold/flu/congestion
15
General pain/inflammation
11
32
LUTS
Severity
Worse
Erectile
Function
AUR=acute urinary retention; IPSS=International Prostate Symptom Score.
N=10,636 men who had been sexually active within the last 4 weeks.
IIEF=International Index of Erectile Function.
McVary KT, et al. BJU Int. 2006;97(suppl s2):23-28.
33
Increased RhoA–
ROCK signaling
Autonomic
hyperactivity
• Reduced function of nerves
and endothelium
• Altered smooth muscle
relaxation or contractility
• Arterial insufficiency, reduced
blood flow, and hypoxia-related
tissue damage
Chronic inflammation
34
What to Keep in Mind in the
Evaluation of LUTS
BPH-LUTS and ED
Common Pathophysiologic Mechanisms
FUNCTIONAL CONSEQUENCES AT TISSUE LEVEL
(corpora cavernosa,
prostate, urethra, and
bladder functional
alterations)
45
Erectile or other sexual dysfunction
Better
Erectile
Function
•
•
•
•
•
Lee RK, et al. BJU Int. 2012;110(4):540-545. Parsons JK. Curr Bladder Dysfunct Rep. 2010;5(4):212-218.
Robert G, et al. Curr Opin Urol. 2011;21(1):42-48. Roehrborn CG. BJU Int. 2006;97 suppl 2:7-11. Rosen R, et al.
Eur Urol. 2003;44(6):637-649. Shabsigh R, et al. BMC Urol. 2010;10:18. Woo HH, et al. Med J Aust. 2011;195(1):34-39.
Reduced NO–
cGMP signaling
High cholesterol
Mean IIEF Erectile
Function Domain
Risk Factors
53
Erectile Function and LUTS Severity
Common Risk Factors and Comorbidities
• Increasing LUTS severity or
symptom worsening
• Increasing serum
dihydrotestosterone
• Enlarged prostate; >30 mL
• Inflammation
• Elevated IPSS
• Refractory to treatment
• Poor flow
• Genetics
• History of AUR
• High waist circumference
• Increasing age
• PSA >1.5 ng/dL
• PVR >50 mL
• Increasing bother
• Reduced physical activity
%
Hypertension
Roehrborn CG, et al; BPH Registry and Patient Survey Steering Committee. BJU Int. 2007;100(4):813-819.
30
LUTS-BPH
Comorbidity with BPH-LUTS
(N=6909)
Pelvic
atherosclerosis
BPH-LUTS
ED
•
Lower Urinary Tract Symptoms (LUTS) can be
of urologic origin, which includes the prostate
and bladder, or can be medical in nature
•
A comprehensive history, physical, and
laboratory evaluation will generally provide the
needed clues
Steroid hormone unbalance
Comorbidities
Hypertension, Metabolic Syndrome, Diabetes, etc
cGMP=cyclic guanosine monophosphate; NO=nitric oxide; ROCK=Rho-associated protein kinase.
Gacci M, et al. Eur Urol. 2011;60(4):809-825.
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
35
5
37
Medications Can Cause or
Exacerbate BPH/LUTS
Examples in the Medical or Surgical History
That Can Cause or Confound LUTS
•
•
Poorly controlled diabetes causing polyuria/polydipsia
Medication
Antihypertensive diuretics can cause frequency and
urgency whereas some cold medications
(eg, α-agonists) commonly cause flow problems
Sedatives
•
Congestive heart failure causing nighttime fluid
mobilization
-Agonists
Increased outlet resistance, voiding difficulty
ß-Blockers
Decreased urethral closure, stress incontinence
•
•
Recent surgery causing immobilization or constipation
Anticholinergics
Angiotensin-converting enzyme
First-generation antihistamines
Cholinesterase inhibitors
38
Abdominal
Neurological
Constipation
– Meatus and testes
•
Urinalysis
•
A random or fasting blood sugar
•
Prostate specific antigen
– Infection, blood, crystals
– The urine is not an adequate screener for diabetes because the blood
sugar must be above 180 mg/dL before it spills into the urine
– Prostate specific, not cancer specific, but can be used in screening
– Excellent as a surrogate marker for prostate size
Rectal
– Tone
• PSA is more accurate than a DRE when estimating prostate size
• A PSA of 1.5 ng/mL equates to a prostate volume of at least 30 grams (mL)
– Prostate size, shape, nodules and consistency
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
Bosch JL, et al. Eur Urol. 2004;46(6):753-759.
Roehrborn CG, et al. Urology. 1999;53(3);581-589.
40
41
International Prostate Symptom
Score (IPSS) Questionnaire
Optional Tests
•
•
•
•
39
– Diabetes
Genitourinary
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
Increase outlet resistance
Precipitate urge incontinence
Laboratory Tests
– Mental and ambulatory status, neuromuscular function
•
Induce cough, stress urinary incontinence
Opioids
– Tenderness, masses, distension
•
Reduce bladder smooth muscle contractility
Newman DK. Nurse Pract. 2009;34(12):33-45.
Dubeau CE. J Urol. 2006;175(3 Pt 2):S11-S15.
Wyman JF, et al. Int J Clin Pract. 2009;63(8):1177-1191.
Gill SS, et al. Arch Intern Med. 2005;165(7):808-813.
Lavelle JP, et al. Am J Med. 2006;119(3 suppl 1):37-40.
A Focused Physical Examination
•
Diuresis
Impaired contractility, voiding difficulty, overflow incontinence
Calcium-channel blockers
The temporal relationship may offer a clue
•
Confusion, secondary incontinence
Alcohol, caffeine, diuretics
Poor urinary hygiene
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
Burgio KL, et al. Int J Clin Pract. 2013;67(6):495-504.
LUTS-Related Effect
International Prostate Symptom Score (IPSS)
Voiding Diary
Post Void Residual (PVR)
Urine Flow Rate (Qmax)
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
McVary KT, et al. J Urol. 2011;185(5):1793-1803. http://www.urospec.com/uro/Forms/ipss.pdf.
Accessed February 12, 2014.
42
6
43
The Purpose of the Voiding Diary
•
•
Post Void Residual
Identifies voiding frequency and volumes
Differentiates behavioral problems as opposed to ones
of pathologic origin
FACTS
•
•
– Voiding frequently after drinking the 40-ounce cola at lunch or
break (behavioral)
– Voiding frequently of small amounts only at work as a result of
always being in a rush (behavioral)
– Voiding frequently of small amounts (OAB)
– Voiding frequently of large amounts (overproduction of fluid –
medical cause or excessive intake)
•
•
WHEN TO CHECK
•
•
•
Alerts the patients as to their habits and may offer
opportunities for improvement
Can help monitor efficacy of treatment
Wyman JF, et al. Int J Clin Pract. 2009;63(8):1177-1191.
Clinical suspicion
Refractory to therapy for BPH
Prior to pharmacologic treatment of OAB
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
AUA Guidelines. http://www.auanet.org/education/guidelines/benign-prostatic-hyperplasia.cfm.
Accessed February 12, 2014.
44
45
The Next STEP
LUTS and Indications for Referral
•
•
•
•
•
•
•
•
•
•
•
50 mL or less represents adequate voiding
200 mL or more is consistent with clinically significant
inadequate voiding
Suspicion of neurologic cause of symptoms
History of recurrent UTI or other infection
Findings or suspicion of urinary retention
Abnormal prostate exam (nodules)
Microscopic or gross hematuria
History of genitourinary trauma
Prior genitourinary surgery
Uncertain diagnosis
Meatal stenosis
Elevated PSA
Pelvic pain
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
47
The Next STEP:
Step 1
48
STEP 1: Informed Surveillance
If the patient has symptoms but no bother and no complications
Patients who opt for this option may benefit from:
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
•
•
•
Lifestyle changes (exercise, weight management)
•
•
Medication modification
Limitations of fluids
Bladder training focused on timed and complete voiding
(behavior modification)
Although LUTS secondary to BPH is not often a lifethreatening condition, the impact of LUTS/BPH on quality of
life (QoL) can be significant and should not be underestimated
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
Burgio KL, et al. Int J Clin Pract. 2013;67(6):495-504.
49
7
50
The Next STEP:
Step 2
Rationale for Alpha-Blocker
or PDE5i Therapy
Alpha-blockers
PDE5i’s
Dynamic component
Rapidly relieve symptoms by
inhibiting contraction of
prostate smooth muscle
PDE5i=phosphodiesterase 5 inhibitor.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
Roehrborn CG. Rev Urol. 2009;11(suppl 1):S1-S8.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
51
Step 2:
Alpha-Blockers (AB)
52
Step 2:
Alpha-Blockers
Single medication therapy with an AB is
appropriate for the symptomatic patient who has
identified bother and has a PSA of <1.5 ng/mL
Non-Uroselective
Uroselective
Terazosin 1, 2, 5, 10 mg daily
Tamsulosin 0.4 mg daily
Doxazosin 1, ,2, 4, 8 mg daily
Alfuzosin 10 mg daily
Silodosin 8 mg daily
•
•
Generally fast acting, relieving symptoms
within days
Does not affect progression of prostate growth
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
Potential side effects
(decreased incidence with uroselective agents)
•
•
•
•
•
•
Asthenia, fatigue, dizziness
Postural hypotension
Congestion, rhinitis, cough
Abnormal ejaculation
Edema
Headache
Physicians’ Desk Reference, 64 ed. Montvale, NJ: Thomson/PDR; 2010.
Lepor H. Rev Urol. 2007;9(4):181-190.
Roehrborn CG. Rev Urol. 2009;11(suppl 1):S1-S8.
53
54
Step 2:
Phosphodiesterase Type 5 Inhibitors
Step 2:
Phosphodiesterase 5 Inhibitors (PDE5i)
Single medication therapy with a PDE5i is appropriate
for the symptomatic patient who has identified bother
and has a PSA of < 1.5 ng/mL. The potential impact of
this therapy on male sexual function should be
considered
Medication
Dose
Tadalafil
2.5 mg per day
Indication
BPH
Tadalafil
5.0 mg per day
BPH and ED
•
•
New as a treatment for BPH-LUTS
Common side effects:
headache, back pain, myalgia, dizziness, flushing, and dyspepsia.
It is believed that the PDE5i increases the signaling of the
NO/cGMP pathway, which reduces smooth muscle tone in the
lower urinary tract
•
Contraindicated in patients who use nitrates, potassium channel openers, or
nonselective 2nd generation ABs. Cardiac status must be assessed for patient
risk before taking this medications.
It is not believed that use of a PDE5i will reduce progression
of prostate growth
Roehrborn CG, et al. J Urol. 2008;180(4):1228-1234.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
Roehrborn CG, et al. J Urol. 2008;180(4):1228-1234.
Oelke M, et al; European Association of Urology. Eur Urol. 2013;64(1):118-140.
Nehra A, et al. Mayo Clin Proc. 2012;87(8):766-778.
Cialis [package insert]. Indianapolis, IN: Eli Lilly & Company; 2011.
55
56
8
The Next STEP:
Step 3a
What About PDE5i’s and ABs?
•
Recent studies show benefit of PDE5i/AB
combination therapy over AB monotherapy
– Improvement in IPSS
– No added benefit in urodynamic parameters
•
Concerns over hemodynamics effects of
combination therapy not demonstrated
Bechara A, et al. J Sex Med. 2008;5(90:2170-2178.
Giuliano F, et al. Urology. 2006;67(6):1199-1204.
Liguori G, et al. J Sex Med. 2009;6(2):544-552.
Kaplan SA, et al. Eur Urol. 2007;51(6):1717-1723.
Gacci M, et al. Eur Urol. 2012;61(5):994-1003.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
57
Rationale for Combining AB/PDE5i
with Antimuscarinic/Beta-3
STEP 3a:
Addition of an Antimuscarinic or Beta-3
Antimuscarinics
Alpha-blockers
If the patient has symptoms of both obstruction and
irritation as well as bother
•
In multiple studies the combination of antimuscarinics were
more efficacious in reducing voiding frequency, nocturia, or
IPSS compared with α-blockers or placebo alone
•
The β3 agonist class is newly available and has not been
studied in combination with an AB.
•
Neither antimuscarinics or β3 agonists have been studied
in combination with PDE5i medications.
Blocks contraction
of detrusor
PDE5i’s
+
Dynamic component
Rapidly relieve symptoms
58
Beta-3 Agonists
Facilitates bladder
storage
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
Oelke M, et al; European Association of Urology. Eur Urol. 2013;64(1):118-140.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
59
Antimuscarinics – Extended Release
Antimuscarinics – Immediate Release
Extended release medications have a better
tolerability than their immediate release counterparts
Exact mechanism of action unknown
(may work on efferent or afferent pathway)
Drug
Drug
Frequency
Frequency
Dose
Dose
Darifenacin
Daily
7.5 mg, 15 mg
Fesoterodine
Daily
4 mg, 8 mg
Oxybutynin ER
Daily
5 – 30 mg
Oxybutynin TDS
Twice per week
3.9 mg
Daily
100 mg
Solifenacin
Daily
5 mg, 10 mg
Tolterodine ER
Daily
5 mg
Trospium Chloride
Daily
60 mg
Oxybutynin IR
2–4 times per day
5 mg
Tolterodine IR
Twice per day
1-2 mg
Trospium Chloride
Twice per day
20 mg
Oxybutynin, 10%, gel
IR=immediate release.
Physicians’ Desk Reference, 64 ed. Montvale, NJ: Thomson/PDR; 2010.
60
ER=extended release; TDS=transdermal delivery system.
Physicians’ Desk Reference, 64 ed. Montvale, NJ: Thomson/PDR; 2010.
61
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62
Common Side Effects
of Antimuscarinics
•
•
•
•
Common Contraindications
of Antimuscarinics
•
•
•
Dry Mouth
Constipation
Headaches
Blurred vision
Urinary or gastric retention
Uncontrolled narrow-angle glaucoma
Clinically significant bladder outlet obstruction
Side effects are greater with the immediate release
medications compared with the extended release
medications
Some patients have symptoms that are severe enough
they would tolerate significant side effects, whereas that
may not be the same for others.
Steers WD. Urol Clin North Am. 2006;33(4):475-482.
Erdem N, et al. Am J. Med. 2006;119(suppl 1):29-36.
Oelke M, et al; European Association of Urology. Eur Urol. 2013;64(1):118-140.
Physicians’ Desk Reference, 64 ed. Montvale, NJ: Thomson/PDR; 2010.
Oelke M, et al; European Association of Urology. Eur Urol. 2013;64(1):118-140. .
63
The Next STEP:
Step 3b
Beta-3 Agonists
Drug
Dosing
Mirabegron
25–50 mg per day
64
Common side effects: hypertension, nasopharyngitis, urinary tract
infections, and headache
Caution should be used in patients with clinically significant bladder
outlet obstruction
Mirabegron [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2012.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
65
Rationale for Combining
AB/PDE5i with 5ARI
66
Step3b:
Adding a 5 Alpha Reductase Inhibitor (5ARI)
The addition of a 5ARI is appropriate for the
symptomatic patient with BPH-LUTS who has identified
bother and has a PSA of 1.5 ng/mL or greater
Alpha-blockers
PDE5i’s
Dynamic component
Rapidly relieve symptoms
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
5-alpha-reductase
inhibitors (5ARIs)
Static component
Arrest disease progression
•
Prostate growth may result in symptoms progression and
other complications
•
Prostate growth is stimulated by dihydrotestosterone (DHT),
with is converted from testosterone by the 5-alpha reductase
enzyme
•
Decreasing DHT may induce prostatic epithelial apoptosis
and atrophy, which can lead to approximately 18%–28%
reduction in prostate size and approximately a 50% reduction
in PSA levels after 6 to 12 months
Naslund MJ, et al. Clin Ther. 2007;29(1):17-25. Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
67
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68
5ARIs
Combination Therapy
Blocks conversion of testosterone to
dihydrotestosterone, thereby inhibiting prostate growth
Drug
Dosage
Finasteride
Dutasteride
5 mg daily
0.5 mg daily
Potential side effects
•
•
•
•
•
Diminished ejaculatory volume
Erectile dysfunction
Decreased libido
Gynecomastia
Increased risk of high-grade prostate cancer*
•
Starting with combination therapy may allow immediate
symptom relief from the AB or a PDE51 while facilitating
prostate reduction from the 5ARI
•
Two prolonged studies (MTOPS and CombaT) using an
AB and a 5ARI have shown that combination therapy is
better than either monotherapy alone
•
One 26-week study showed that use of tadalafil with
finasteride was better than finasteride alone
•
Expert opinion supports the long-term use of
combination therapy in the patient with an enlarged
prostate
CombaT=Combination of Avodart and Tamsulosin; MTOPS=Medical Therapy of Prostatic Symptoms.
*Conflicting data in the literature
Physicians’ Desk Reference, 64 ed. Montvale, NJ: Thomson/PDR; 2010.
Andriole G, et al. J Urol. 2004;172(4 Pt 1):1399-1403.
Thompson IM Jr, et al. N Engl J Med. 2013;369(7):603-610.
Crawford ED, et al. J Urol. 2006;175(4):1422-1427. Roehrborn CG, et al; CombAT Study Group. Eur Urol.
2009;55(2):461-471. Kaplan SA, et al; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. J Urol.
2006;175(1):217-220. Roehrborn CG, et al. 28th Annual EAU Congress; Milan, Italy; 15-19 March 2013.
69
The Next STEP:
Step 4
Combination Therapy of an AB with a 5ARI
Outperforms Either Monotherapy Alone
IPSS – Adjusted Mean Change From Baseline (LOCF)
0
-1
Tamsulosin (n=1582)
Dutasteride (n=1592)
Combination (n=1575)
-2
Change (units)
70
-3
-3.8
-4
-5
-5.3
-6
-6.3
-7
P<.001 Combination vs Tamsulosin
P<.001 Combination vs Dutasteride
-8
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
Treatment month
LOCF=last observation carried forward.
Roehrborn CG, et al; CombAT Study Group. Eur Urol. 2010;57(1):123-131.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
71
Step 4:
Referral
SUMMARY
For the patient with symptoms and bother who
is refractory to therapy
Understanding the facts simplifies the
evaluation and treatment in BPH/LUTS
•
•
The symptoms and comorbidities of BPH/LUTS provide
significant clues
•
•
The pathophysiology helps to define those at risk
•
There are many treatment options available for the PCP,
including alpha blockers, 5ARIs and PDE-5 inhibitors
•
“Alarm symptoms” or “red flags” (hematuria, acute
urinary retention, UTI, bladder stones, renal failure)
Failure to respond in a reasonable amount of time
warrants reevaluation and possible referral
– Alpha blockers, PDE5i’s, antimuscarinics, and β3 agonists
should work quickly
– 5ARIs work slowly
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
Rosenberg MT, et al. Curr Urol Rep. 2013;14(6):595-605.
73
74
The assessment is readily done in the office of the PCP
without the need for extensive testing
75
11